CN117883371A - Gatifloxacin eye drops and preparation method thereof - Google Patents
Gatifloxacin eye drops and preparation method thereof Download PDFInfo
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- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 title claims abstract description 74
- 229960003923 gatifloxacin Drugs 0.000 title claims abstract description 74
- 239000003889 eye drop Substances 0.000 title claims abstract description 52
- 229940012356 eye drops Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 81
- 239000000243 solution Substances 0.000 claims abstract description 64
- 239000008215 water for injection Substances 0.000 claims abstract description 55
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical class [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims abstract description 45
- 239000012528 membrane Substances 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 238000001914 filtration Methods 0.000 claims abstract description 22
- 230000003204 osmotic effect Effects 0.000 claims abstract description 21
- 239000007924 injection Substances 0.000 claims abstract description 15
- 238000002347 injection Methods 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims description 45
- 238000003756 stirring Methods 0.000 claims description 42
- 239000007788 liquid Substances 0.000 claims description 41
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 239000000284 extract Substances 0.000 claims description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 24
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 20
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000011010 flushing procedure Methods 0.000 claims description 18
- 239000000419 plant extract Substances 0.000 claims description 18
- 240000005125 Myrtus communis Species 0.000 claims description 17
- 235000013418 Myrtus communis Nutrition 0.000 claims description 17
- 235000007516 Chrysanthemum Nutrition 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000004310 lactic acid Substances 0.000 claims description 12
- 235000014655 lactic acid Nutrition 0.000 claims description 12
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 238000005303 weighing Methods 0.000 claims description 12
- 229940064064 purslane extract Drugs 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- YVYNLIHIATTZSH-UHFFFAOYSA-N [Na+].Cl[Cl-]Cl Chemical compound [Na+].Cl[Cl-]Cl YVYNLIHIATTZSH-UHFFFAOYSA-N 0.000 claims description 6
- 239000010408 film Substances 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- 230000001502 supplementing effect Effects 0.000 claims description 6
- 244000189548 Chrysanthemum x morifolium Species 0.000 claims 1
- 229940113058 gatifloxacin ophthalmic solution Drugs 0.000 claims 1
- 229960002233 benzalkonium bromide Drugs 0.000 abstract description 6
- 238000013329 compounding Methods 0.000 abstract description 3
- 230000007797 corrosion Effects 0.000 abstract description 3
- 238000005260 corrosion Methods 0.000 abstract description 3
- 230000036512 infertility Effects 0.000 abstract description 3
- 230000007794 irritation Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000001954 sterilising effect Effects 0.000 abstract description 3
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 3
- 241000723353 Chrysanthemum Species 0.000 description 12
- 229940079593 drug Drugs 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 206010059866 Drug resistance Diseases 0.000 description 4
- 239000012982 microporous membrane Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000000022 bacteriostatic agent Substances 0.000 description 3
- 230000003385 bacteriostatic effect Effects 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 241000194107 Bacillus megaterium Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 238000000194 supercritical-fluid extraction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010061788 Corneal infection Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018795 Prunus mume Species 0.000 description 1
- 235000011158 Prunus mume Nutrition 0.000 description 1
- 241000519590 Pseudoalteromonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- XUBOMFCQGDBHNK-UHFFFAOYSA-N gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCNC(C)C1 XUBOMFCQGDBHNK-UHFFFAOYSA-N 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229960001957 stomatological preparations Drugs 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 229940109235 zymar Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses gatifloxacin eye drops and a preparation method thereof, wherein the gatifloxacin eye drops comprise the following components: gatifloxacin, modified benzalkonium bromide solution, solubilizer, osmotic pressure regulator, and water for injection; the specific formula comprises the following components: 3.0-5.0g of gatifloxacin, 1.2-4.4ml of modified benzalkonium bromide solution, 1.5-4.5ml of solubilizer, 5-10g of osmotic pressure regulator and 1000ml of injection water; the invention can greatly reduce the irritation of the product by modifying the benzalkonium bromide solution and compounding with gatifloxacin, a solubilizer and an osmotic pressure regulator, does not influence the bacteriostasis and the corrosion resistance, and ensures the sterility requirement of the preparation by adopting a production process of filter membrane sterilization filtration and aseptic operation.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to gatifloxacin eye drops and a preparation method thereof.
Background
The gatifloxacin bulk drug is a new generation fluoroquinolone drug containing 8-methoxy group which is first developed by Japanese apricot forest pharmaceutical Co., ltd, and the research of toxicology pharmacology and drug generation is formally started in month 2 of 1990, and the clinical test in phase I is started in month 7 of 1991. Clinical studies II and III are carried out in succession beginning in 1 month of 1992, and the clinical study is focused on patients suffering from respiratory tract infection, urinary tract infection and the like. Clinical studies on patients with surgical, dermatological, otorhinolaryngological, gynecological, ophthalmic, dental, and stomatological infections were initiated 8 months in 1993, followed by double blind comparison studies on complex urinary tract infections. The month 12 2000 was approved by the FDA in the united states, where it was first marketed, and formulations were divided into two major types, oral and intravenous.
Gatifloxacin eye drops were also developed by japan apricot forest pharmaceutical co. In japan, the product is licensed to kushou pharmaceutical corporation, and in the united states, the drug is licensed to alaukin (Allergan) pharmaceutical company. The drug was also approved by the FDA in the united states at 31, 3/2003, and was first marketed in the united states under the name Zymar.
The gatifloxacin eye drops belong to fourth-generation fluoroquinolone eye drops, and are compared with the first-generation norfloxacin; the second generation ciprofloxacin, ofloxacin, lomefloxacin and the third generation levofloxacin eye drops are more excellent and have higher activity than other antibiotics such as gentamicin, kanamycin, neomycin, polymyxin and the like which are used clinically. The medicines have drug resistance and cross drug resistance to certain bacteria such as staphylococcus aureus, pseudomonas aeruginosa, escherichia coli and the like, but the bacteria have no drug resistance and cross drug resistance to gatifloxacin eye drops, and in addition, the gatifloxacin eye drops have good treatment effects on chlamydia, mycoplasma, keratitis caused by infection and the like.
The gatifloxacin eye drops on the market all contain bacteriostats, and once opened, are easily polluted by tears and microorganisms in the air in the using and preserving processes, so that potential safety hazards are generated. In order to prevent the ophthalmic preparation from being secondarily polluted by microorganisms in the process of repeated use after unsealing, the ophthalmic preparation is added with a bacteriostatic agent, and almost all eye drops in the Chinese medical hospital preparation standard are used. The currently commonly used bacteriostatic agents for eye drops are benzalkonium chloride, benzalkonium bromide, parahydroxybenzoate and the like, and are also called preservative agents. The currently used preservative or bacteriostatic agent has weak bacteriostatic ability and narrow bacteriostatic spectrum, and the bacteriostatic effect of the preservative is not ideal, see Chinese practical medicine, 2010,5 (24) and P43-44. Although gatifloxacin has a certain antibacterial effect, the antibacterial effect cannot be used as a judging standard of whether an antibacterial agent is added to an ophthalmic preparation, see the medicine evaluation center of the national food and drug administration, and consider that no antibacterial agent is added to a multi-dose ophthalmic preparation, and the electronic journal is 9 and 12 in 2008.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide gatifloxacin eye drops and a preparation method thereof so as to solve the problems in the prior art.
The invention solves the technical problems by adopting the following technical scheme:
the invention provides gatifloxacin eye drops, which comprise the following components: gatifloxacin, modified benzalkonium bromide solution, solubilizer, osmotic pressure regulator, and water for injection;
the specific formula comprises the following components: 3.0 to 5.0g of gatifloxacin, 1.2 to 4.4ml of modified benzalkonium bromide solution, 1.5 to 4.5ml of solubilizer, 5 to 10g of osmotic pressure regulator and 1000ml of water for injection.
Preferably, the content of the gatifloxacin is 0.5-0.8%, and the unit is g/mL.
Preferably, the pH value of the eye drops is 5.0-7.0.
Preferably, the modified benzalkonium bromide solution comprises the following components in percentage by mass: 0.05 to 0.1 percent of benzalkonium chloride, 1.2 to 4.6 percent of plant extract, 1 to 3 percent of film forming agent and the balance of water.
Preferably, the film forming agent comprises 1-3 parts of polyvinyl alcohol and 7-10 parts of water in parts by weight.
Preferably, the plant extract comprises myrtle extract, chrysanthemum extract and purslane extract, and the weight ratio of the myrtle extract to the chrysanthemum extract to the purslane extract is (0.4-0.8): (1-1.8): (2.5-3.5).
The myrtle extract is prepared by pulverizing myrtle leaf to obtain myrtle leaf powder, mixing the myrtle leaf powder with water according to a feed liquid ratio of 1g: mixing 10-15mL, adding bacillus megatherium for fermentation, wherein the mass ratio of bacillus megatherium to myrtle leaf powder is 0.15-0.35:1, the fermentation condition is 26-34 ℃, the humidity is 50-60%, the fermentation time is 8-10d, the fermented myrtle leaf powder is extracted by adopting a supercritical extraction method, the pressure of the supercritical extraction method is 20-25MPa, the extraction temperature is 38-42 ℃, the extraction time is 30-50min, and the CO2 flow is 8-10mL/min;
the preparation method of the chrysanthemum extract comprises the steps of adopting an ultrasonic extraction process, wherein the ultrasonic power is 180-220W, the extraction solvent is ethanol solution with the mass concentration of 40-50%, the extraction temperature is 80-90 ℃, the extraction time is 20-25min, and the ratio of the extraction solvent to the chrysanthemum material liquid is 1g/15-20mL;
the preparation method of herba Portulacae extract comprises pulverizing herba Portulacae, collecting filtrate and residue, adding pseudoalteromonas, fermenting for 3-5d, leaching fermented herba Portulacae at 60-65deg.C for 3-5h, collecting extractive solution, filtering filtrate with macroporous resin, and concentrating filtrate at 80-90deg.C for 8-12min to obtain herba Portulacae extract.
Preferably, the preparation method of the modified benzalkonium bromide solution comprises the following steps:
s1, adding 50-60% of injection water of the prescription mass into a preparation tank, adding benzalkonium chloride, and stirring at the temperature of 12-16 ℃ for 15-30min at the speed of 100-200r/min to prepare benzalkonium chloride primary preparation liquid;
s2, mixing polyvinyl alcohol and water to prepare a film forming agent;
s3, adding enough water for injection, plant extract and film forming agent, and stirring at 8-12 ℃ for 4-10min at 300-500 r/min.
Preferably, the solubilizer is lactic acid and the osmolality adjusting agent is 0.9% sodium chloride solution.
The invention also provides a preparation method of the gatifloxacin eye drops, which comprises the following steps:
precisely weighing gatifloxacin, adding lactic acid prepared first, stirring, adding 400ml of water for injection, slightly heating and stirring, adding modified benzalkonium bromide solution, stirring uniformly to obtain liquid medicine I,
filtering the liquid medicine obtained in the first step by using a microporous filter membrane, flushing the filter membrane by using a small amount of water for injection, and collecting filtrate and flushing fluid;
precisely weighing 0.9% sodium chloride for injection, dissolving in 200ml of water for injection, slightly heating, stirring to dissolve, filtering with microporous filter membrane, and flushing the filter membrane with a small amount of water for injection;
adding the main medicine containing gatifloxacin and the modified benzalkonium bromide solution into the sodium trichloride solution, uniformly stirring, measuring the content, adding water for injection to 950-980mL according to the concentration of gatifloxacin of 0.5-0.8%, adjusting the PH to 5.0-7.0, and supplementing the water for injection to 1000mL to obtain a second medicine liquid;
and fifthly, filtering the liquid medicine obtained in the step four by using a double-layer microporous filter membrane under the aseptic condition, filling the liquid medicine into sterilized eye drops bottles, and filling the bottles.
Preferably, the specification of the microporous filter membrane is preferably 0.22 μm, and 5% hydrochloric acid and/or 5% sodium hydroxide solution is used for adjusting the pH in the fourth step.
Compared with the prior art, the invention has the following beneficial effects:
the invention can greatly reduce the irritation of the product by modifying the benzalkonium bromide solution and compounding with gatifloxacin, a solubilizer and an osmotic pressure regulator, does not influence the bacteriostasis and the corrosion resistance, and ensures the sterility requirement of the preparation by adopting a production process of filter membrane sterilization filtration and aseptic operation.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides gatifloxacin eye drops, which comprise the following components: gatifloxacin, modified benzalkonium bromide solution, solubilizer, osmotic pressure regulator, and water for injection;
the specific formula comprises the following components: 3.0 to 5.0g of gatifloxacin, 1.2 to 4.4ml of modified benzalkonium bromide solution, 1.5 to 4.5ml of solubilizer, 5 to 10g of osmotic pressure regulator and 1000ml of water for injection.
The content of gatifloxacin in this example is 0.5-0.8% in g/mL.
The pH of the eye drops of this example is 5.0-7.0.
The modified benzalkonium bromide solution of the embodiment comprises the following components in percentage by mass: 0.05 to 0.1 percent of benzalkonium chloride, 1.2 to 4.6 percent of plant extract, 1 to 3 percent of film forming agent and the balance of water.
The film forming agent of the embodiment comprises 1-3 parts by weight of polyvinyl alcohol and 7-10 parts by weight of water.
The plant extracts of this example include myrtle extract, chrysanthemum extract and purslane extract, the weight ratio of myrtle extract, chrysanthemum extract and purslane extract is (0.4-0.8): (1-1.8): (2.5-3.5).
The preparation method of the modified benzalkonium bromide solution in the embodiment comprises the following steps:
s1, adding 50-60% of injection water of the prescription mass into a preparation tank, adding benzalkonium chloride, and stirring at the temperature of 12-16 ℃ for 15-30min at the speed of 100-200r/min to prepare benzalkonium chloride primary preparation liquid;
s2, mixing polyvinyl alcohol and water to prepare a film forming agent;
s3, adding enough water for injection, plant extract and film forming agent, and stirring at 8-12 ℃ for 4-10min at 300-500 r/min.
The solubilizing agent of this example was lactic acid and the osmotic pressure regulator was 0.9% sodium chloride solution.
The preparation method of the gatifloxacin eye drops comprises the following steps:
precisely weighing gatifloxacin, adding lactic acid prepared first, stirring, adding 400ml of water for injection, slightly heating and stirring, adding modified benzalkonium bromide solution, stirring uniformly to obtain liquid medicine I,
filtering the liquid medicine obtained in the first step by using a microporous filter membrane, flushing the filter membrane by using a small amount of water for injection, and collecting filtrate and flushing fluid;
precisely weighing 0.9% sodium chloride for injection, dissolving in 200ml of water for injection, slightly heating, stirring to dissolve, filtering with microporous filter membrane, and flushing the filter membrane with a small amount of water for injection;
adding the main medicine containing gatifloxacin and the modified benzalkonium bromide solution into the sodium trichloride solution, uniformly stirring, measuring the content, adding water for injection to 950-980mL according to the concentration of gatifloxacin of 0.5-0.8%, adjusting the PH to 5.0-7.0, and supplementing the water for injection to 1000mL to obtain a second medicine liquid;
and fifthly, filtering the liquid medicine obtained in the step four by using a double-layer microporous filter membrane under the aseptic condition, filling the liquid medicine into sterilized eye drops bottles, and filling the bottles.
The microporous membrane of this example is preferably 0.22 μm in size, and 5% hydrochloric acid and/or 5% sodium hydroxide solution is used for adjusting the pH in the fourth step.
Example 1.
The invention provides gatifloxacin eye drops, which comprise the following components: gatifloxacin, modified benzalkonium bromide solution, solubilizer, osmotic pressure regulator, and water for injection;
the specific formula comprises the following components: 3.0g of gatifloxacin, 1.2ml of modified benzalkonium bromide solution, 1.5ml of solubilizer, 5g of osmotic pressure regulator and 1000ml of water for injection.
The gatifloxacin content in this example was 0.5% in g/mL.
The pH of the eye drop of this example was 5.0.
The modified benzalkonium bromide solution of the embodiment comprises the following components in percentage by mass: 0.05% of benzalkonium chloride, 1.2% of plant extract, 1% of film forming agent and the balance of water.
The film forming agent of this example comprises, by weight, 1 part of polyvinyl alcohol and 7 parts of water.
The plant extracts of this example include myrtle extract, chrysanthemum extract and purslane extract, the weight ratio of myrtle extract, chrysanthemum extract and purslane extract is 0.4:1:2.5.
the preparation method of the modified benzalkonium bromide solution in the embodiment comprises the following steps:
s1, adding 50% of injection water of the prescription mass into a preparation liquid tank, adding benzalkonium chloride, and stirring at the temperature of 12 ℃ for 15min at the speed of 100r/min to prepare benzalkonium chloride primary preparation liquid;
s2, mixing polyvinyl alcohol and water to prepare a film forming agent;
s3, adding enough water for injection, plant extract and film forming agent, and stirring at 300r/min for 4min at 8 ℃ to obtain the injection.
The solubilizing agent of this example was lactic acid and the osmotic pressure regulator was 0.9% sodium chloride solution.
The preparation method of the gatifloxacin eye drops comprises the following steps:
precisely weighing gatifloxacin, adding lactic acid prepared first, stirring, adding 400ml of water for injection, slightly heating and stirring, adding modified benzalkonium bromide solution, stirring uniformly to obtain liquid medicine I,
filtering the liquid medicine obtained in the first step by using a microporous filter membrane, flushing the filter membrane by using a small amount of water for injection, and collecting filtrate and flushing fluid;
precisely weighing 0.9% sodium chloride for injection, dissolving in 200ml of water for injection, slightly heating, stirring to dissolve, filtering with microporous filter membrane, and flushing the filter membrane with a small amount of water for injection;
adding the main medicine containing gatifloxacin and the modified benzalkonium bromide solution into the sodium trichloride solution, uniformly stirring, measuring the content, adding water for injection to 950mL according to the concentration of gatifloxacin of 0.5%, adjusting the pH to 5.0, and supplementing the water for injection to 1000mL to obtain a second medicine liquid;
and fifthly, filtering the liquid medicine obtained in the step four by using a double-layer microporous filter membrane under the aseptic condition, filling the liquid medicine into sterilized eye drops bottles, and filling the bottles.
The microporous membrane of this example is preferably 0.22 μm in size, and 5% hydrochloric acid and/or 5% sodium hydroxide solution is used for adjusting the pH in the fourth step.
Example 2.
The invention provides gatifloxacin eye drops, which comprise the following components: gatifloxacin, modified benzalkonium bromide solution, solubilizer, osmotic pressure regulator, and water for injection;
the specific formula comprises the following components: 5.0g of gatifloxacin, 4.4ml of modified benzalkonium bromide solution, 4.5ml of solubilizer, 10g of osmotic pressure regulator and 1000ml of water for injection.
The gatifloxacin content in this example was 0.8% in g/mL.
The PH of the eye drop of this example was 7.0.
The modified benzalkonium bromide solution of the embodiment comprises the following components in percentage by mass: 0.1% of benzalkonium chloride, 4.6% of plant extract, 3% of film forming agent and the balance of water.
The film forming agent of this example comprises 3 parts by weight of polyvinyl alcohol and 10 parts by weight of water.
The plant extracts of this example include myrtle extract, chrysanthemum extract and purslane extract, the weight ratio of myrtle extract, chrysanthemum extract and purslane extract is 0.8:1.8:3.5.
the preparation method of the modified benzalkonium bromide solution in the embodiment comprises the following steps:
s1, adding 60% of injection water of the prescription mass into a preparation liquid tank, adding benzalkonium chloride, and stirring at the temperature of 16 ℃ for 30min at the speed of 200r/min to prepare benzalkonium chloride primary preparation liquid;
s2, mixing polyvinyl alcohol and water to prepare a film forming agent;
s3, adding enough water for injection, plant extract and film forming agent, and stirring at 500r/min for 4-10min at 12 ℃ to obtain the final product.
The solubilizing agent of this example was lactic acid and the osmotic pressure regulator was 0.9% sodium chloride solution.
The preparation method of the gatifloxacin eye drops comprises the following steps:
precisely weighing gatifloxacin, adding lactic acid prepared first, stirring, adding 400ml of water for injection, slightly heating and stirring, adding modified benzalkonium bromide solution, stirring uniformly to obtain liquid medicine I,
filtering the liquid medicine obtained in the first step by using a microporous filter membrane, flushing the filter membrane by using a small amount of water for injection, and collecting filtrate and flushing fluid;
precisely weighing 0.9% sodium chloride for injection, dissolving in 200ml of water for injection, slightly heating, stirring to dissolve, filtering with microporous filter membrane, and flushing the filter membrane with a small amount of water for injection;
adding the main medicine containing gatifloxacin and the modified benzalkonium bromide solution into the sodium trichloride solution, uniformly stirring, measuring the content, adding water for injection to 980mL according to the concentration of gatifloxacin, adjusting the pH to 7.0, and supplementing the water for injection to 1000mL to obtain a second medicine liquid;
and fifthly, filtering the liquid medicine obtained in the step four by using a double-layer microporous filter membrane under the aseptic condition, filling the liquid medicine into sterilized eye drops bottles, and filling the bottles.
The microporous membrane of this example is preferably 0.22 μm in size, and 5% hydrochloric acid and/or 5% sodium hydroxide solution is used for adjusting the pH in the fourth step.
Example 3.
The invention provides gatifloxacin eye drops, which comprise the following components: gatifloxacin, modified benzalkonium bromide solution, solubilizer, osmotic pressure regulator, and water for injection;
the specific formula comprises the following components: gatifloxacin 4.0g, modified benzalkonium bromide solution 2.8ml, solubilizer 3.0ml, osmotic pressure regulator 7.5g, water for injection 1000ml.
The gatifloxacin content in this example was 0.65% in g/mL.
The pH of the eye drop of this example was 6.0.
The modified benzalkonium bromide solution of the embodiment comprises the following components in percentage by mass: 0.08% of benzalkonium chloride, 2.9% of plant extract, 2% of film forming agent and the balance of water.
The film forming agent of this example comprises 2 parts by weight of polyvinyl alcohol and 8.5 parts by weight of water.
The plant extracts of this example include myrtle extract, chrysanthemum extract and purslane extract, the weight ratio of myrtle extract, chrysanthemum extract and purslane extract is 0.6:1.4:3.
the preparation method of the modified benzalkonium bromide solution in the embodiment comprises the following steps:
s1, adding 55% of injection water of the prescription mass into a preparation liquid tank, adding benzalkonium chloride, and stirring at 150r/min for 23min at 14 ℃ to prepare benzalkonium chloride primary preparation liquid;
s2, mixing polyvinyl alcohol and water to prepare a film forming agent;
s3, adding enough water for injection, plant extract and film forming agent, and stirring at 400r/min for 7min at 10 ℃ to obtain the injection.
The solubilizing agent of this example was lactic acid and the osmotic pressure regulator was 0.9% sodium chloride solution.
The preparation method of the gatifloxacin eye drops comprises the following steps:
precisely weighing gatifloxacin, adding lactic acid prepared first, stirring, adding 400ml of water for injection, slightly heating and stirring, adding modified benzalkonium bromide solution, stirring uniformly to obtain liquid medicine I,
filtering the liquid medicine obtained in the first step by using a microporous filter membrane, flushing the filter membrane by using a small amount of water for injection, and collecting filtrate and flushing fluid;
precisely weighing 0.9% sodium chloride for injection, dissolving in 200ml of water for injection, slightly heating, stirring to dissolve, filtering with microporous filter membrane, and flushing the filter membrane with a small amount of water for injection;
adding the main medicine containing gatifloxacin and the modified benzalkonium bromide solution into the sodium trichloride solution, uniformly stirring, measuring the content, adding water for injection to 965mL according to the concentration of gatifloxacin of 0.75%, adjusting the pH to 6.0, and supplementing the water for injection to 1000mL to obtain a second medicine liquid;
and fifthly, filtering the liquid medicine obtained in the step four by using a double-layer microporous filter membrane under the aseptic condition, filling the liquid medicine into sterilized eye drops bottles, and filling the bottles.
The microporous membrane of this example is preferably 0.22 μm in size, and 5% hydrochloric acid and/or 5% sodium hydroxide solution is used for adjusting the pH in the fourth step.
Comparative example 1.
The difference from example 3 is that the benzalkonium bromide solution was not modified.
Comparative example 2.
Unlike example 3, no solubilizer was added.
Comparative example 3.
The difference from example 3 is that the content of benzalkonium chloride in the modified benzalkonium bromide solution component was 0.02%.
The gatifloxacin eye drops prepared in examples 1 to 3 and comparative examples 1 to 3 were tested:
stability of
The products prepared in examples 1-3 and comparative examples 1-3 were left at 25.+ -. 5 ℃ for 3 months and each of the examination indexes was compared with 0 day, and the test data are shown in the following table.
According to the table, various investigation indexes of the eye drops prepared by the invention have no obvious change compared with the eye drops prepared by 0 day, the eye drops have good stability, and meanwhile, the properties of the eye drops are obviously changed due to the fact that the benzalkonium bromide solution is not modified in comparative example 1, so that the eye drops are proved to be unusable.
The invention can greatly reduce the irritation of the product by modifying the benzalkonium bromide solution and compounding with gatifloxacin, a solubilizer and an osmotic pressure regulator, does not influence the bacteriostasis and the corrosion resistance, and ensures the sterility requirement of the preparation by adopting a production process of filter membrane sterilization filtration and aseptic operation.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (10)
1. The gatifloxacin eye drop is characterized by comprising the following components: gatifloxacin, modified benzalkonium bromide solution, solubilizer, osmotic pressure regulator, and water for injection;
the specific formula comprises the following components: 3.0 to 5.0g of gatifloxacin, 1.2 to 4.4ml of modified benzalkonium bromide solution, 1.5 to 4.5ml of solubilizer, 5 to 10g of osmotic pressure regulator and 1000ml of water for injection.
2. The gatifloxacin eye drop according to claim 1, wherein the gatifloxacin is present in an amount of 0.5-0.8% expressed in g/mL.
3. The gatifloxacin eye drop according to claim 1, wherein the PH of the eye drop is between 5.0 and 7.0.
4. The gatifloxacin eye drop according to claim 1, wherein the modified benzalkonium bromide solution comprises the following components in percentage by mass: 0.05 to 0.1 percent of benzalkonium chloride, 1.2 to 4.6 percent of plant extract, 1 to 3 percent of film forming agent and the balance of water.
5. The gatifloxacin eye drop of claim 4 wherein the film forming agent comprises 1-3 parts by weight of polyvinyl alcohol and 7-10 parts by weight of water.
6. The gatifloxacin eye drop of claim 4 wherein the plant extracts comprise myrtle extract, chrysanthemum extract and purslane extract in a weight ratio of (0.4-0.8): (1-1.8): (2.5-3.5).
7. The gatifloxacin eye drop according to claim 1, wherein the preparation method of the modified benzalkonium bromide solution comprises the following steps:
s1, adding 50-60% of injection water of the prescription mass into a preparation tank, adding benzalkonium chloride, and stirring at the temperature of 12-16 ℃ for 15-30min at the speed of 100-200r/min to prepare benzalkonium chloride primary preparation liquid;
s2, mixing polyvinyl alcohol and water to prepare a film forming agent;
s3, adding enough water for injection, plant extract and film forming agent, and stirring at 8-12 ℃ for 4-10min at 300-500 r/min.
8. The gatifloxacin eye drop according to claim 1, wherein the solubilizer is lactic acid and the osmolality adjusting agent is 0.9% sodium chloride solution.
9. The method for preparing gatifloxacin ophthalmic solution according to any one of claims 1 to 8, characterized in that it comprises the following steps:
precisely weighing gatifloxacin, adding lactic acid prepared first, stirring, adding 400ml of water for injection, slightly heating and stirring, adding modified benzalkonium bromide solution, stirring uniformly to obtain liquid medicine I,
filtering the liquid medicine obtained in the first step by using a microporous filter membrane, flushing the filter membrane by using a small amount of water for injection, and collecting filtrate and flushing fluid;
precisely weighing 0.9% sodium chloride for injection, dissolving in 200ml of water for injection, slightly heating, stirring to dissolve, filtering with microporous filter membrane, and flushing the filter membrane with a small amount of water for injection;
adding the main medicine containing gatifloxacin and the modified benzalkonium bromide solution into the sodium trichloride solution, uniformly stirring, measuring the content, adding water for injection to 950-980mL according to the concentration of gatifloxacin of 0.5-0.8%, adjusting the PH to 5.0-7.0, and supplementing the water for injection to 1000mL to obtain a second medicine liquid;
and fifthly, filtering the liquid medicine obtained in the step four by using a double-layer microporous filter membrane under the aseptic condition, filling the liquid medicine into sterilized eye drops bottles, and filling the bottles.
10. The method for preparing gatifloxacin eye drop according to claim 9, wherein the size of the microporous filter membrane is preferably 0.22 μm, and wherein in the fourth step, 5% hydrochloric acid and/or 5% sodium hydroxide solution is used for adjusting the pH.
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